WO2018065826A1 - Billes multicouches à usage pharmaceutique - Google Patents

Billes multicouches à usage pharmaceutique Download PDF

Info

Publication number
WO2018065826A1
WO2018065826A1 PCT/IB2017/001383 IB2017001383W WO2018065826A1 WO 2018065826 A1 WO2018065826 A1 WO 2018065826A1 IB 2017001383 W IB2017001383 W IB 2017001383W WO 2018065826 A1 WO2018065826 A1 WO 2018065826A1
Authority
WO
WIPO (PCT)
Prior art keywords
drug
polymer
multilayer
per
layer
Prior art date
Application number
PCT/IB2017/001383
Other languages
English (en)
Inventor
Deepak Tiwari
Yasuhiro Harada
Ryu Hirata
Original Assignee
Sucampo Ag
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Sucampo Ag filed Critical Sucampo Ag
Priority to US16/338,948 priority Critical patent/US11534404B2/en
Priority to JP2019516182A priority patent/JP6957610B2/ja
Publication of WO2018065826A1 publication Critical patent/WO2018065826A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/167—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface
    • A61K9/1676—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface having a drug-free core with discrete complete coating layer containing drug
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
    • A61K31/558—Eicosanoids, e.g. leukotrienes or prostaglandins having heterocyclic rings containing oxygen as the only ring hetero atom, e.g. thromboxanes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1611—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/10—Laxatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration

Definitions

  • the invention relates to multilayer beads, and processes for their preparation, and pharmaceutical uses thereof. More particularly, the invention relates to multilayer beads having a drug-in-polymer layer where the drug is a 15-keto prostaglandin drug, a 13,14-dihydro prostaglandin drug, or a 13,14-dihydro-15-keto prostaglandin drug and the polymer is polyvinylpyrrolidone, vinylpyrrolidone-vinylacetate copolymer or a mixture thereof and used to treat gastrointestinal disorders.
  • Fatty acid derivatives are found in tissues or organs of humans and other mammals, and exhibit a wide range of physiological activities.
  • Prostaglandins are a type of fatty acid derivative, having a prostanoic acid skeleton as shown in the formula (A):
  • Some synthetic prostaglandin (PG) analogues have modified prostanoic acid skeletons and various chemical modifications.
  • the primary structures of such analogues are classified as PGAs, PGBs, PGCs, PGDs, PGEs, PGFs, PGGs, PGHs, PGIs and PGJs according to the five- membered ring moiety, and they can be further classified into subtypes by the number and position of an unsaturated bond on the omega chain.
  • PGEi Proliferatives of PGEi are used to treat gastrointestinal disorders.
  • 15-keto- 16-halogen prostaglandin compounds are useful as cathartics (U.S. Pat. No. 5,317,032).
  • Lubiprostone also known as 13,14-dihydro-15-keto-16,16-difluoro-PGEi, is the active pharmaceutical ingredient ("API” or "drug substance") in the Amitiza ® drug product used for the treatment of conditions such as chronic idiopathic constipation, opioid-induced
  • Lubiprostone activates the Type 2 Chloride Channel (CIC-2) and increases chloride-rich fluid secretion from the serosal to the mucosal side of the gastrointestinal tract.
  • CIC-2 Type 2 Chloride Channel
  • prostaglandins are insoluble in water and become significantly unstable in the presence of water. Moreover, prostaglandins are unstable themselves or in the presence of most solids or solvents.
  • an encapsulated formulation comprising a 15-keto-16-difluoro prostaglandin compound and a solvent such as glyceride, which can maintain the stability of the compound, was described (U.S. Pat. No. 6,583,174).
  • Amitiza is formulated with medium chain fatty acid triglycerides (MCTs) in a soft-gelatin capsule with a high shelf stability as described in U.S. Pat. No. 8,026,393.
  • the invention relates to multilayer beads for pharmaceutical use having a drug-in- polymer layer where the drug is a 15-keto prostaglandin drug, a 13,14-dihydro prostaglandin drug, or a 13,14-dihydro-15-keto prostaglandin drug and the polymer is polyvinylpyrrolidone, vinylpyrrolidone-vinylacetate copolymer or a mixture thereof. More broadly, the invention is applicable to fatty acid derivatives used as drugs and described in Formula I of US Pat. No. 8,026,393, the contents of which are expressly incorporated by reference. The invention also relates to pharmaceutical compositions containing a plurality of the multilayer beads and are used to treat gastrointestinal disorders, especially gastrointestinal disorders in children, the elderly and individuals with dysphagia.
  • the invention provides multilayer beads for pharmaceutical use comprising:
  • the drug-in-polymer layer consists essentially of:
  • a drug selected from the group consisting of a 15-keto prostaglandin drug, a 13,14- dihydro prostaglandin drug, and a 13,14-dihydro-15-keto prostaglandin drug;
  • an optional sealant layer coated on the surface of the drug-in-polymer layer (d) an optional sealant layer coated on the surface of the drug-in-polymer layer; and (e) optionally, one or more outer layers external to the drug-in-polymer layer or, when present, the sealant layer.
  • the invention provides pharmaceutical compositions comprising a plurality of multilayer beads and a pharmaceutically acceptable excipient.
  • the plurality of multilayer beads in combination represent a therapeutically effective amount of the drug and may be a unit dose of the drug.
  • Such a pharmaceutical composition is usually presented in the form of a solid oral dosage form.
  • the invention also relates to methods of treating a gastrointestinal disorder comprising the step of orally administering to a patient in need thereof a therapeutically effective amount of the multilayer beads in a pharmaceutical composition of according to the invention.
  • Another embodiment of the invention relates to a solid formulation or a solid dispersion of a drug in a polymer consisting essentially of (a) a drug selected from the group consisting of a 15-keto prostaglandin drug, a 13,14-dihydro prostaglandin drug, and a 13,14-dihydro-15-keto prostaglandin drug; and (b) a polymer selected from the group consisting of
  • Fig. 1 depicts a multi-layer bead of the invention.
  • Fig. 2 depicts the dissolution profile described in Example 10.
  • the invention relates to multilayer beads for pharmaceutical use having a drug-in- polymer layer where the drug is a 15-keto prostaglandin drug, a 13,14-dihydro prostaglandin drug, or a 13,14-dihydro-15-keto prostaglandin drug and the polymer is polyvinylpyrrolidone, vinylpyrrolidone-vinylacetate copolymer or a mixture thereof. More broadly, the invention is applicable to fatty acid derivatives used as drugs and described in Formula I of US Pat. No. 8,026,393, the contents of which are expressly incorporated by reference.
  • the invention is based on a finding that such beads and drug formulations are surprisingly effective to stabilize the drug and to prevent it from migrating outside of the drug-in-polymer layer.
  • the invention also relates to pharmaceutical compositions containing a plurality of the multilayer beads and are used to treat gastrointestinal disorders, especially gastrointestinal disorders in children and the elderly.
  • 15-keto prostaglandin drugs, 13,14-dihydro prostaglandin drugs and 13,14-dihydro-15- keto prostaglandin drugs are known in the art and are known to be effective in treating gastrointestinal disorders. These drugs, which are derivatives of fatty acids, are described in published PCT application WO 2016/067620 and US Patent 6,414,016; the disclosures of which are incorporated herein by reference. Representative examples of these drugs include but are not limited to:
  • a 15-keto prostaglandin drug, a 13,14-dihydro prostaglandin drug and a 13,14-dihydro-15-keto prostaglandin drug includes the drug itself, a pharmaceutically acceptable salt of the drug, or a metabolite or prodrug of the drug, as well as isomers (including tautomeric isomers) of the drug and mixtures of isomers.
  • the drug is lubiprostone and includes its pharmaceutically acceptable salts, isomers, metabolites or prodrugs.
  • 15-hydroxy lubiprostone is a metabolite of lubiprostone, as described in US Patent No. 6,956,056.
  • an amide prodrug of lubiprostone is described in US Patent No. 7,064,148.
  • the invention relates to multilayer beads for pharmaceutical use which contain a 15- keto prostaglandin drug, a 13,14-dihydro prostaglandin drug, or a 13,14-dihydro-15-keto prostaglandin drug as the active pharmaceutical ingredient (API).
  • Fig. 1 depicts a multi-layer bead of the invention. I n a multilayer bead of the invention there is:
  • barrier layer (b) an optional barrier layer [102] coated on the surface of the core particle; (c) a drug-in-polymer layer [103] coated on the surface of the core particle or, when present, the barrier layer,
  • the drug-in-polymer layer consists essentially of:
  • a drug selected from the group consisting of a 15-keto prostaglandin drug, a 13,14-dihydro prostaglandin drug, and a 13,14-dihydro-15-keto prostaglandin drug;
  • a polymer selected from the group consisting of polyvinylpyrrolidone, vinylpyrrolidone-vinylacetate copolymer or a mixture thereof;
  • a multilayered bead typically has a maximum size of about 2000 to about 3000 microns in diameter or along its longest axis.
  • the maximum size is about 500 to about 1000 microns or the maximum size is about 700 to about 950 microns.
  • a multilayer bead is typically spherical or spheroidal in shape but may have another shape such as, for example, an elongated shape or a lozenge shape.
  • the diameter or longest axis of a multilayer bead of the invention should comply with the USFDA size requirements for administration to children or as a sprinkle formulation.
  • the target bead size is up to 2.5 mm with no more than a 10 percent variation over that size to a maximum size of 2.8 mm.
  • the amount of drug present in a multilayered bead of the invention may range from about 0.01 ⁇ g to about 0.2 ⁇ g, from about 0.02 ⁇ g to about 0.1 ⁇ g, or from about 0.04 ⁇ g to about 0.08 ⁇ g, although the amount in each bead may be adapted to the therapeutically desired dose and the number of beads present in a particular pharmaceutical composition.
  • the core particle [101] may be any core particle used in the pharmaceutical arts to make beaded formulations. Spherical or spheroidal particles are generally used but the core particle may be of any shape that can be coated with the other layers of the multilayer bead of the invention.
  • the core particle may have a diameter or longest axis in the range of about 100- 1,500 ⁇ , of about 200-700 ⁇ or of about 350-500 ⁇ .
  • Exemplary core particles that may be used in a multilayer bead of the invention are microcrystalline cellulose particles, silica particles and sugar particles. Microcrystalline cellulose particles having a spherical shape and a range of diameters are sold under the Cellets ® tradename.
  • Cellets ® 100 are spherical microcrystalline cellulose spheres having a particle size ranging from 100-200 ⁇
  • Cellets ® 350 are spherical microcrystalline cellulose spheres having a particle size ranging from 350-500 ⁇
  • Cellets ® 500 are spherical microcrystalline cellulose spheres having a particle size ranging from 500-710 ⁇
  • Cellets ® 1000 are spherical microcrystalline cellulose spheres having a particle size ranging from 1000-1400 ⁇ .
  • an optional barrier layer [102] may be coated on the surface of the core particle.
  • the purpose of this barrier layer is to separate the drug-in- polymer layer [103] from the core particle [101] and to minimize or prevent contact of the drug with the core. As shown below in Example la, contact of the drug with the core particle [101] may cause degradation of the drug and a loss of potency for the pharmaceutical formulation.
  • the barrier layer is typically a polymeric layer. Any pharmaceutically acceptable polymer which performs the desired function of the barrier layer may be used.
  • the polymers are polyvinylpyrrolidone (PVP), vinylpyrrolidone-vinylacetate copolymer (PVP-VA or a mixture thereof.
  • PVP and PVP-VA are commercially available, for example, Kollidon ® 17PF and Kollidon ® VA, manufactured by BASF. Any commercially-available, pharmaceutically acceptable PVP or PVP-VA or combinations thereof may be used for the polymer matrix.
  • the 15-keto prostaglandin drugs, 13,14-dihydro prostaglandin drugs, or 13,14-dihydro- 15-keto prostaglandin drugs which are the APIs in a multilayer bead of the invention are located in the drug-in-polymer layer [103].
  • a drug-in-polymer layer according to the invention consists essentially of (i) a drug selected from the group consisting of a 15-keto prostaglandin drug, a 13,14-dihydro prostaglandin drug, and a 13,14-dihydro-15-keto prostaglandin drug; and (ii) a polymer selected from the group consisting of polyvinylpyrrolidone, vinylpyrrolidone- vinylacetate copolymer or a mixture thereof.
  • the drug may exist as an amorphous solid or crystalline solid, or the drug may be molecularly dissolved in the solid excipient matrix.
  • the drug is present in the drug-in-polymer layer in a relative amount of drug to polymer ranging from about 1 part drug per 0.2 part polymer up to about 1 part drug per 200 parts polymer, per 400 parts polymer, per 500 parts polymer per 1,000 parts polymer, and per 10,000 parts polymer.
  • the drug-in-polymer layer [103] may be a simple admixture of the drug and polymer or a solid dispersion of the drug in the polymer.
  • a solid dispersion is a solid composition having at least two components where one component is dispersed in a matrix of another component.
  • the drug is dispersed as a solid in the polymeric matrix.
  • a solid dispersion, as used herein, also includes a solid solution, wherein one component is molecularly dissolved in the solid matrix of the other component.
  • the drug is molecularly dissolved in the excipient matrix.
  • the drug-in-polymer layer [103] consists essentially of the drug and the polymer.
  • the layer may, like the other layers in a multilayer bead of the invention, contain processing aids or excipients such as those discussed below.
  • the drug-in-polymer layer [103] should not contain components which would mobilize the drug within the layer such that it might leach from into other layers of the multilayer bead or otherwise degrade.
  • Such drug-in-polymer mixtures do not contain excipients which can affect the stability of the drug in the drug-in-polymer layer such that the drug retains therapeutic efficacy. It has been found that a drug-in-polymer layer and a multilayer bead of the invention are particularly stable even under stress stability testing conditions.
  • a multilayer bead of the invention After exposure to storage conditions for 10 days at 55 °C, a multilayer bead of the invention retains at least 75-80% of the pharmaceutically efficacy or potency of the drug.
  • the multilayer beads of the invention remain in a state or condition that is suitable for administration to a patient and are therapeutically efficacious without potentially interfering deterioration products.
  • an optional sealant layer [104] may be coated on the surface of the drug-in-polymer layer [103].
  • the purpose of this sealant layer is to separate the drug-in-polymer layer [103] from the outer layer(s) [105], when present, and to minimize or prevent the drug from leaching from the multilayer bead.
  • contact of the drug with an outer layer polymer may cause degradation of the drug and a loss of potency for the pharmaceutical formulation.
  • the sealant layer is typically a polymeric layer. Any pharmaceutically acceptable polymer which performs the desired function of the sealant layer may be used.
  • Exemplary polymers are polyvinylpyrrolidone (PVP), vinylpyrrolidone-vinylacetate copolymer (PVP-VA) or a mixture thereof.
  • PVP polyvinylpyrrolidone
  • PVP-VA vinylpyrrolidone-vinylacetate copolymer
  • Various standardized PVP and PVP-VA are commercially available, for example, Kollidon ® 17PF and Kollidon ® VA, manufactured by BASF. Any commercially-available, pharmaceutically acceptable PVP or PVP-VA or combinations thereof may be used for the polymer matrix.
  • the same polymer may make up the barrier layer [103], the drug-in-polymer layer [103] and the sealant layer [104] when they are present.
  • the polymers in all three of these layers may be polyvinylpyrrolidone, vinylpyrrolidone-vinylacetate copolymer or a mixture thereof.
  • the barrier layer [102] and the sealant layer [104] sandwich the drug-in-polymer layer [104] using the same polymer or mixture of polymers.
  • barrier layer [103]/drug-in-polymer layer [103]/sealant layer [104] may be maintained to achieve the purposes of the layers and the stability of the multilayer bead.
  • a multilayer bead of the invention optionally also may contain one or more outer layers [105] to modify its release and/or taste properties, to reduce water and oxygen permeation, and/or to provide mechanical to the particle to withstand breaking or chipping.
  • Such coatings are known in the art.
  • a coating which masks taste or prevents dissolution at neutral pH but allows rapid dissolution in acidic environment may be used to prevent dissolution or disintegration of a multilayer bead until it reaches a gastric environment after being administered as part of a pharmaceutical composition.
  • Such polymers are, for example, insoluble at a pH ranging from 6 to 8 and soluble at pH ranging from 1 to 5 or insoluble at a pH ranging from 5 to 8 and soluble at pH ranging from 1 to 4.
  • the outer layer comprises a copolymer comprising butyl methacrylate.
  • EUDRAGIT ® E100 a copolymer of dimethylaminoethyl methacrylate, butylmethacrylate and methyl methacrylate, is used as the outer layer.
  • the layers of a multilayer bead may contain additives for coating ease as selected from pharmaceutically acceptable excipients as is known in the art.
  • one or more of the layers may contain plasticizers and lubricants such as PEGs and polyethylene glycol.
  • Plasticizers include, for example, glycerin, acetyl tributyl citrate, polyethylene glycols, acetyl triethyl citrate, polyethylene glycol monomethyl ether, castor oil propylene glycol, diacetylated monoglycerides, sorbitol sorbitan solution, dibutyl sebacate, diethyl phthalate, triacetin, tributyl citrate and triethyl citrate.
  • each layer may be sprinkled with anti-static or static-reducers such as talc and silicon dioxide.
  • a multilayer bead of the invention there is:
  • the drug-in-polymer layer consists essentially of:
  • a drug selected from the group consisting of a 15-keto prostaglandin drug, a 13,14-dihydro prostaglandin drug, and a 13,14-dihydro-15-keto prostaglandin drug;
  • a polymer selected from the group consisting of polyvinylpyrrolidone, vinylpyrrolidone-vinylacetate copolymer or a mixture thereof;
  • the drug may be lubiprostone (or a pharmaceutically acceptable salt, isomer, metabolite or prodrug thereof).
  • a multilayer bead of the invention is prepared by sequential coating of the core particles with the indicated layers using coating techniques known in the art, such as in a fluidized bed coating apparatus. Each layer may be applied sequentially as a solution or dispersion of its components and then dried to remove the solvent prior to applying the next coating. Individual layers are spray coated using solvent.
  • An exemplary solvent used for spray coating is acetone. The spray coating may beconducted at a temperature not exceeding 30°C. The coated layers are dried at a temperature not exceeding 45°C.
  • the invention also relates to pharmaceutical compositions comprising a plurality of multilayer beads according to the invention and a pharmaceutically acceptable excipient.
  • a pharmaceutical composition of the invention may be an oral dosage form or a packaging of the multilayered beads that can be opened and the beads administered.
  • the plurality of multilayer beads may be contained in a capsule, sachet or pouch.
  • the invention also relates to a solid formulation of a drug in a polymer.
  • the solid formulation of a drug in a polymer may be a simple admixture of the drug and polymer or a solid dispersion of the drug in the polymer.
  • a solid formulation of a drug in polymer according to the invention is a solid dispersion consisting essentially of (a) a drug selected from the group consisting of a 15-keto prostaglandin drug, a 13,14-dihydro prostaglandin drug, and a 13,14- dihydro-15-keto prostaglandin drug; and (b) a polymer selected from the group consisting of polyvinylpyrrolidone, vinylpyrrolidone-vinylacetate copolymer or a mixture thereof.
  • Another solid formulation of a drug in a polymer according to the invention is an admixture consisting essentially of (a) a drug selected from the group consisting of a 15-keto prostaglandin drug, a 13,14-dihydro prostaglandin drug, and a 13,14-dihydro-15-keto prostaglandin drug; and (b) a polymer selected from the group consisting of polyvinylpyrrolidone, vinylpyrrolidone- vinylacetate copolymer or a mixture thereof.
  • a solid formulation of a drug in a polymer according to the invention may be in the form of a particle and consist essentially of (a) a drug selected from the group consisting of a 15-keto prostaglandin drug, a 13,14-dihydro prostaglandin drug, and a 13,14-dihydro-15-keto prostaglandin drug; and (b) a polymer selected from the group consisting of
  • polyvinylpyrrolidone vinylpyrrolidone-vinylacetate copolymer or a mixture thereof.
  • a person skilled in the art would be able to select an appropriate particle size depending on the mode of administration, the pharmaceutical formulation containing the solid formulation, and manufacturing parameters. As an upper limit, the particle itself may be as large as
  • the invention also relates to pharmaceutical compositions containing a solid formulation of a drug in a polymer combined with pharmaceutically acceptable excipients.
  • the solid formulations of a drug in a polymer may be in particle formconsisting essentially of (a) a drug selected from the group consisting of a 15-keto prostaglandin drug, a 13,14-dihydro prostaglandin drug, and a 13,14-dihydro-15-keto prostaglandin drug; and (b) a polymer selected from the group consisting of
  • the solid formulation of the drug in a polymer may form the core of a multilayer bead or of a single dosage form both with one or more of the layers discussed above.
  • the pharmaceutical composition may contain a plurality of multilayer beads.
  • compositions of the invention may be prepared by methods known in the pharmaceutical formulation art, for example, see Remington's Pharmaceutical Sciences, 18th Ed., (Mack Publishing Company, Easton, Pa., 1990), which is incorporated herein by reference.
  • the layers of the bead other than the drug-in-polymer layers, and the multilayer beads themselves in a dosage form may be admixed with at least one pharmaceutically acceptable excipient such as, for example, sodium citrate or dicalcium phosphate or (a) fillers or extenders, such as, for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders, such as, for example, cellulose derivatives, starch, aliginates, gelatin,
  • polyvinylpyrrolidone sucrose, and gum acacia
  • humectants such as, for example, glycerol
  • disintegrating agents such as, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, croscarmellose sodium, complex silicates, and sodium carbonate
  • solution retarders such as, for example, paraffin
  • absorption accelerators such as, for example, quaternary ammonium compounds
  • wetting agents such as, for example, cetyl alcohol, and glycerol monostearate, magnesium stearate and the like
  • adsorbents such as, for example, kaolin and bentonite
  • lubricants such as, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof.
  • the dosage forms may also comprise buffering agents.
  • Acceptable excipients may also be present in between adjacent layers of the multilayer beads.
  • excipients may be present in between the outer layer and sealant layer, in between the sealant layer and drug-in-polymer layer, in between the drug-in- polymer layer and barrier layer, in between the barrier layer and the core, or combinations thereof.
  • compositions of the invention may also be used in the pharmaceutical compositions of the invention. These include, but are not limited to, preserving, wetting, suspending, sweetening, flavoring, perfuming, emulsifying, and dispensing agents. Prevention of the action of microorganisms may be ensured by inclusion of various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example, sugars, sodium chloride, and the like.
  • a pharmaceutical composition of the invention may also contain minor amounts of auxiliary substances such as wetting or emulsifying agents, pH buffering agents, antioxidants, and the like, such as, for example, citric acid, sorbitan monolaurate, triethanolamine oleate, butylated hydroxytoluene, etc.
  • auxiliary substances such as wetting or emulsifying agents, pH buffering agents, antioxidants, and the like, such as, for example, citric acid, sorbitan monolaurate, triethanolamine oleate, butylated hydroxytoluene, etc.
  • a pharmaceutical composition of the invention may be an oral dosage form containing a plurality of multilayered beads and other excipients to allow transport, storage and distribution.
  • the dosage form may comprise the beads in free-flowing form or in the form of a tablet, such as a fast disintegrating tablet releasing the multilayer beads.
  • a fast disintegrating tablet may for example, include a disintegrant in addition to the multilayer beads.
  • a pharmaceutical composition of the invention may also be a solid dosage form, for example, a tablet or hard capsule, prepared, for example, as a solid solution of lubiprostone together with PVP or PVP-PA as described in the examples below.
  • Such solid dosage forms can be made to be capable of releasing at least about 70% of the amount of drug comprised in the dosage form within 30 minutes when measured in a USP type 2 dissolution apparatus in 810 ml neutral water and 90ml of IN HCI at 37°C and 200 rpm.
  • Solid dosage forms for oral administration such as capsules and tablets are known in the art and may be prepared by any methods well known in the art of pharmacy. See, for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Philadelphia, Pa. (18th ed. 1990).
  • a tablet may be made by compression or molding, optimally with one or more excipient.
  • Compressed tablets may be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a excipient such as a binder, lubricant, inert diluent, preservative, surface-active or dispersing agent.
  • Molded tablets may be made by molding, in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets may optionally be coated or scored and may be formulated so as to provide a slow or controlled release of the active ingredient therein.
  • a capsule dosage form of the invention can be a hard capsule, and is generally made from animal-derived gelatin or plant-derived hydroxypropyl methylcellulose (HPMC).
  • HPMC hydroxypropyl methylcellulose
  • the size of a capsule for an oral dosage form of the invention can be any size that is sufficient to contain its components.
  • the capsule can be a size 5, 4, 3, 2, 1, 0, 0E, 00, 000, 13, 12, 12el, 11, 10, 7, or Su07. Capsules are filled using any suitable techniques known in the art.
  • the plurality of multilayer beads in combination within the pharmaceutical composition comprise a therapeutically effective amount of the drug to be administered to a patent in need thereof.
  • the multilayer beads may be dose packed (or dosed by another appropriate dosing device, such as measuring spoon).
  • the amount of drug present in a plurality of multilayered beads in a pharmaceutical composition of the invention may range from about 1 ⁇ g to about 75 ⁇ g, from about 4 ⁇ g to about 50 ⁇ g, or from about 8 ⁇ g to about 25 ⁇ g or in particular 8, 12, 16 or 24 ⁇ g.
  • a unit dose of the drug is about 1 ⁇ g to about 1,500 ⁇ g, such as for example, about 1 ⁇ g to about 100 ⁇ g, such as for example, from 8 ⁇ g to about 72 ⁇ g.
  • a pharmaceutical composition of the invention includes unit dosage forms of, for example, 8, 12, 16, 24, 48 or 72 ⁇ g, of lubiprostone (or a pharmaceutically acceptable salt, isomer, metabolite or prodrug thereof).
  • the invention also relates to methods of treating a gastrointestinal disorder comprising the step of orally administering to a patient in need thereof a therapeutically effective amount of the multilayer beads in a pharmaceutical composition of the invention. Accordingly, the invention relates to uses of a pharmaceutical composition of the invention to treat a gastrointestinal disorder.
  • gastrointestinal disorder is constipation
  • other gastrointestinal disorders include but are not limited to those associated with a dysfunctional Type 2 Chloride Channels including the disorders chronic idiopathic constipation, opioid- induced constipation, and irritable bowel syndrome with constipation.
  • a gastrointestinal disorder treated may also be an inflammatory bowel disease, such as for example, ulcerative colitis or Crohn's disease.
  • formulations according to the present invention may be administered to treat gastrointestinal disorders for which the administration of lubiprostone has been approved or may be approved in the future by various national regulatory agencies.
  • Such indications include but are not limited to: (a) the treatment of chronic idiopathic constipation (CIC) in adults; (b) the treatment of opioid-induced constipation (OIC) in adults with chronic, non-cancer pain; (c) the treatment of pediatric functional constipation (PFC) in patients aged 6 to 17 years (pending FDA approval in US at the time this application was filed); and (d) the treatment of irritable bowel syndrome with constipation (IBS-C) in women > 18 years old.
  • CIC chronic idiopathic constipation
  • OIC opioid-induced constipation
  • PFC pediatric functional constipation
  • IBS-C irritable bowel syndrome with constipation
  • Dysphagia can occur in various disorders, for example, such as post-polio syndrome, multiple sclerosis, muscular dystrophy, Parkinson's disease, polymyositis, dermatomyositis, esophageal spasm and scleroderma.
  • Treatment of or “treating a gastrointestinal disorder” includes any means of therapeutic control such as prevention, care, relief of symptoms, attenuation of symptoms and arrest of progression.
  • the treatment may be "long term” involving administering a
  • composition of the invention for time periods of at least two weeks, of at least three weeks, of at least one month, or at least two months or of at least six months to one year or longer.
  • the pharmaceutical composition may be administered every day for the whole term of the treatment or with an interval of one to several days as well as once or multiple times per day.
  • a “therapeutically effective amount of a drug” refers to an amount of drug that elicits a therapeutically useful response in a patient in need thereof.
  • the patient is typically a human patient but may also include other mammals such as horses, companion animals (dogs or cats), livestock and zoo animals under veterinary care.
  • a “therapeutically effective amount” may be determined based on the age, body weight, conditions of the patient to be treated, desired therapeutic effect, administration route, treatment period and the like.
  • lubiprostone or a pharmaceutically acceptable salt, isomer, metabolite or prodrug thereof
  • therapeutically effective amounts of lubiprostone may for example, be 4, 8, 12 or 24 ⁇ g once, twice or three times daily, or 48 ⁇ g once or twice daily.
  • a method of treatment or use of a pharmaceutical composition may include the steps of sprinkling the multilayer beads the pharmaceutical formulation into water or onto a soft food substance, and having the patient swallow the water or soft food substance with the sprinkled multilayer beads. This is particularly useful when treating gastrointestinal disorders in pediatric or geriatric patients and in the treatment of individuals aged 0-17 and/or individuals suffering from dysphagia.
  • the multilayer beads also may be sprinkled into water (or another appropriate beverage) which may be stirred or shaken to form a suspension of the multilayer beads prior to swallowing.
  • Soft food substances require only minimal or no chewing and include, but are not limited to, foods such as apple sauce, yogurt, ice cream, cottage cheese, baby food, baby formula, etc.
  • a plurality of multilayer beads may be sprinkled into water and/or apple sauce.
  • the multilayered beads of the invention ca n be made to be capable of resisting the release of the drug for at least about one to fifteen minutes following exposure to water or soft food substance.
  • the multilayer particles and pharmaceutical compositions of the invention thus delay or prevent drug release into neutral suspension vehicles and in vivo prior to reaching stomach.
  • Pharmaceutical compositions of the invention comprising the multilayer beads result in a reduction for adverse events related to nausea and vomiting when compared to prior gel capsule formulations.
  • Colloidal Silica Aerosil ® R972 Pharma, a high purity, amorphous, anhyd
  • Microcrystalline cellulose particles (MCC spheres): Cellets ® 350 spherical microcrystalline cellulose spheres having a particle size ranging from 350-500 ⁇ , available from Glatt Pharmaceutical Services.
  • DBS Dibutyl sebacate
  • plasticizer which is oil (and not a solid material), available from Aldrich.
  • Eudragit E100 anionic copolymer based on methacrylic acid and methylmethacrylate, manufactured by Evonik Nutrition & Care GmbH.
  • PVP Polyvinylpyrrolidone
  • PVP-VA Polyvinylpyrrolidone-vinyl acetate copolymer
  • Copovidone Kollidon ® VA64 USP
  • Lactose Lactose Monohydrate USP/JP, available from Maruishi Pharmaceutical.
  • HPC Hydroxy propyl cellulose
  • USP/JP avairable from Nippon Soda.
  • HPMC Hydroxy propyl methyl cellulose
  • Microcrystalline cellulose powder (MCC powder): CEOLUS ® UF-702, manufactured by Asahi Kasei.
  • Magnesium aluminate metasillicate (MgAMS), avairable from Tomita Pharmaceutical.
  • Test samples were prepared for the study in approximately 50:50 proportion using various excipients and lubiprostone drug. These prepared mixtures were then placed on accelerated stress stability conditions at 55°C for 10 days. After 10 days, these samples were analyzed by a suitable HPLC method to determine assay (the amount of remaining
  • Example IB Lubiprostone-Excipient Contact Stability Study (Solid Solution) [062] Additional test samples were prepared for the study by admixing various excipients and lubiprostone drug in ratios of about 50:50 and about 99:1. Solid solutions were prepared by mixing lubiprostone /MeCN and Excipient/MeCN, combining these mixtures and then removing the solvent by evaporation. The prepared mixtures were then placed under accelerated stress stability conditions at 55°C for 10 days. After 10 days, these samples were analyzed by HPLC method to determine the amount of remaining lubiprostone and impurities generated as a result of the degradation of lubiprostone.
  • Example 1C Lubiprostone-Excipient Contact Stability Study (Mechanical Mixing of Powder)
  • Test samples were prepared by direct (mechanical) mixing of various excipients and lubiprostone drug in approximately 50:50 and 99:1 ratios.
  • the mechanical mixing of lubiprostone and excipients was conduct by admixing them using a conventional mortar.
  • the prepared mixtures were then placed under accelerated stress stability conditions at 55°C for 10 days. After 10 days, these samples were analyzed by HPLC to determine the amount of remaining lubiprostone and impurities generated as a result of the degradation of lubiprostone.
  • Table 1C The observed stability increases for lubiprostone as a result of the mechanical mixing of powders was seen only with PVP and PVP-VA.
  • the stability increase was not as substantial as that observed in Example IB for solid solutions. Without being held to any particular explanation, it is believed that this result was due to relatively less complete mixing.
  • Lubiprostone/polymer solutions were prepared at 10 wt% solids in acetone (HPLC grade, EMD). About 2.5 g of each polymer solution was transferred into aluminum pans ( ⁇ 10 cm diameter) and dried at 40 °C for at least 4 hours, in order to form drug/polymer layers of about 100 ⁇ thickness. The resulting films were examined visually for film integrity. All films were then placed in a forced air convection oven at 55 °C and examined for appearance changes after 10 days. The appearance of each individual drug/polymer film are summarized in Table 2.
  • Spherical microcrystalline cellulose particles (Cellets ® 350) were sequentially covered by a polymer barrier (PVP or PVP-VA) layer, a lubiprostone (Lubi)/polymer layer, a seal coat (PVP or PVP-VA) and a water barrier outer layer (polymethacrylates Eudragit E 100), using a bottom- spray fluidized bed (VFC-LAB Micro Flo-coater) coating process at 30-60 g scale.
  • Table 3 reports the polymers, spray solution concentrations, solvent systems, and process parameters including bed temperature (Tbed), solution feed rate (Q) and nozzle atomizing pressure (P).
  • Coating weight was calculated by dividing the weight of polymer layer by total product weight (i.e., weight of polymer layer and substrate).
  • a secondary tray drying step was conducted at 40 °C overnight in a forced convection oven after coating each layer to remove residual acetone.
  • Coated beads were prepared as described in Example 3.
  • the sequential particle size of the beads before and after coating was determined by laser diffraction using a Malvern Mastersizer 300 with an Aero S unit (Malvern Instruments).
  • D10, D50 and D90 diameters were used to characterize the particle size distribution of powders.
  • the D50 diameter is the diameter at which 50% of a sample's mass is comprised of smaller particles.
  • the particle size of the final products was generally smaller than 1 mm, which is a suitable size for oral suspension dosing in water or for sprinkling on soft foods.
  • a two-stage dissolution testing (i.e., neutral pH -> gastric pH) was conducted on coated beads prepared as described in Example 3 using a Distek Model 2100C USP type 2 dissolution apparatus to simulate the dosing process and a neutral dissolution medium (HPLC grade water with 1% Kolliphor RH40, BASF) preheated to 37. Cf C. All the experiments were conducted in two replicates. Analysis of samples was carried out using HPLC-MS. All three formulations show negligible drug release after being agitated in neutral dissolution medium for 1 hour and almost immediate drug release after adding IN HCI to the medium. This indicates that multilayer beads are not only insoluble in neutral pH water but also has minimal water permeability under such conditions and then quickly dissolve once the surrounding pH decreases to gastric pH, and release drug into the medium.
  • step (c) adding and mixing the solutions from step (b) with talc;
  • step (i) spraying the beads with solution from step (h); (j) drying the beads after the second coating layer; (k) further drying the beads to remove solvent;
  • Example 7 Method of Multilayer Bead Preparation
  • Table 7 Another exemplary composition of multilayer bead of the invention is described in Table 7.
  • Multilayer beads of the invention were tested for stability under stressed conditions.
  • the beads were kept at 55°C for 10 days in glass vials for stability determinations.
  • a two-stage dissolution testing i.e., neutral pH -> gastric pH
  • Dissolution testing was conducted as directed under the Paddle method (Apparatus 2), Dissolution (USP ⁇ 711>) in a HCO-40: Polyoxyl 40 hydrogenated castor oil medium (known as Kolliphor RH40 (BASF)) at 37°C.
  • Table 8 shows amount of lubiprostone remaining, appearance of related degradation substances and dissolution performance for lubiprostone beads prepared as described in Example 7. The amounts of lubiprostone and related degradation substances were assayed by HPLC.
  • Stage 1 Target - Not more than 20% of the labeled amount is released in 30 mins in water with surfactant (1% HCO- 40); Stage 2 Target - Not less than 60% (Q) of the labeled amount is released in 60 mins in 0.1 N HCI with surfactant (1% HCO-40).
  • Example 9 Pharmaceutical Composition: Sprinkle Beads Capsule
  • Multilayer beads of the invention were mixed with 0.5 wt% talc. Size 0 hypromellose blue/white sprinkle capsules are filled with the multilayer beads and talc mixture.
  • a two-stage dissolution testing (i.e., neutral pH -> gastric pH, described above) was conducted on a sprinkle bead capsule containing lubiprostone beads prepared as above.
  • Multilayer beads from the capsule were sprinkled into the dissolution medium, and dissolution testing was conducted as described in Example 8.
  • Figure 2 shows the dissolution profile with minimal to no drug release in the neutral aqueous environment and that the entire remaining drug is released in an acidic environment (like the stomach).
  • Example 11 Stability and Dissolution of Sprinkle Beads Capsule
  • the stability study was conducted using HDPE screw top bottles with desiccant. Stability data for up to 3 months at 252C/60% RH and at 40 ⁇ 0/75% RH is shown in Tables 9 and 10. As shown below, the batch shows good stability.

Landscapes

  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Epidemiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Inorganic Chemistry (AREA)
  • Obesity (AREA)
  • Hematology (AREA)
  • Diabetes (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne des billes multicouches à usage pharmaceutique ayant une couche de médicament dans un polymère. Les billes multicouches décrites pour une utilisation pharmaceutique ont (a) une particule noyau; (b) une couche barrière facultative revêtue sur la surface de la particule noyau; (c) une couche de médicament dans le polymère appliquée sur la surface du noyau ou de la couche barrière, (d) une couche d'agent d'étanchéité facultative revêtue sur la surface de la couche de médicament dans le polymère; et (e) éventuellement une ou plusieurs couches externes à la couche de médicament dans le polymère ou à la couche d'agent d'étanchéité. La couche de médicament dans le polymère consiste essentiellement en (i) un médicament choisi dans le groupe constitué par un médicament à base de 15-céto-prostaglandine, un médicament à base de 13,14-dihydro-prostaglandine, et un médicament à base de 13,14-dihydro-15-céto-prostaglandine; et (ii) un polymère choisi dans le groupe constitué par la polyvinylpyrrolidone, le copolymère de vinylpyrrolidone-vinylacétate ou un mélange de ceux-ci. La couche de médicament dans le polymère peut être dispersion solide du médicament dans le polymère. L'invention concerne également des compositions pharmaceutiques comprenant une pluralité de billes multicouches et un excipient pharmaceutiquement acceptable et des procédés de traitement d'un trouble gastro-intestinal.
PCT/IB2017/001383 2016-10-06 2017-10-05 Billes multicouches à usage pharmaceutique WO2018065826A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
US16/338,948 US11534404B2 (en) 2016-10-06 2017-10-05 Multilayer beads for pharmaceutical use
JP2019516182A JP6957610B2 (ja) 2016-10-06 2017-10-05 医薬品用途のための多層ビーズ

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201662405131P 2016-10-06 2016-10-06
US62/405,131 2016-10-06

Publications (1)

Publication Number Publication Date
WO2018065826A1 true WO2018065826A1 (fr) 2018-04-12

Family

ID=60543581

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2017/001383 WO2018065826A1 (fr) 2016-10-06 2017-10-05 Billes multicouches à usage pharmaceutique

Country Status (5)

Country Link
US (1) US11534404B2 (fr)
JP (1) JP6957610B2 (fr)
AR (1) AR109898A1 (fr)
TW (1) TW201815383A (fr)
WO (1) WO2018065826A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109701461A (zh) * 2018-10-25 2019-05-03 西南交通大学 一种基于PEG/Dex双水相的碳酸钙/海藻酸钙复合微囊的制备及其应用
JP2020075874A (ja) * 2018-11-06 2020-05-21 ニプロ株式会社 ルビプロストン含有フィルム状医薬組成物
JPWO2019221215A1 (ja) * 2018-05-18 2021-05-27 ニプロ株式会社 ルビプロストン含有粒子状医薬組成物
US11382865B2 (en) * 2016-12-09 2022-07-12 Bayer Animal Health Gmbh Pharmaceutical preparation and method for its manufacture
US11534404B2 (en) 2016-10-06 2022-12-27 Sucampo Ag Multilayer beads for pharmaceutical use

Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5252605A (en) * 1991-03-14 1993-10-12 R-Tech Ueno Ltd. Promotion of wound-healing with 15-keto-prostaglandin compounds
US5317032A (en) 1987-10-02 1994-05-31 Kabushiki Kaisha Ueno Seiyaku Oyo Kenkyujo Prostaglandin cathartic
WO2001076593A2 (fr) * 2000-04-06 2001-10-18 Sucampo Ag Composition favorisant la secretion biliaire
US6414016B1 (en) 2000-09-05 2002-07-02 Sucampo, A.G. Anti-constipation composition
WO2002089812A1 (fr) * 2001-05-02 2002-11-14 Sucampo Ag Composition comprenant des 15-ceto-prostaglandines permettant de traiter la constipation d'origine medicamenteuse
US6583174B1 (en) 1999-10-15 2003-06-24 Sucampo, A.G. Composition and method for stabilizing the same
US6956056B2 (en) 2001-05-18 2005-10-18 Sucampo Ag Method for providing a cathartic effect
US7064148B2 (en) 2001-08-31 2006-06-20 Sucampo Ag Chloride channel opener
WO2007086536A2 (fr) * 2006-01-24 2007-08-02 R-Tech Ueno, Ltd. Formulation de capsule gélatineuse molle
EP2275419A2 (fr) * 2008-04-01 2011-01-19 Shanghai Techwell Biopharmaceutical Co., Ltd. Cristal de lubiprostone, son procédé de préparation et son utilisation
WO2016067620A1 (fr) 2014-10-30 2016-05-06 Sucampo Ag Procédé et composition pour le traitement de la maladie du reflux non érosif

Family Cites Families (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5942313A (ja) * 1982-09-01 1984-03-08 Teijin Ltd ポリビニルポリピロリドンを用いた製剤
JPS6377821A (ja) * 1986-09-19 1988-04-08 Teikoku Seiyaku Kk 安定なプロスタグランジンｅ組成物
DE19962544A1 (de) 1999-12-23 2001-07-19 Degussa Verfahren zum Beschichten eines keramischen Wabenkörpers
JP2005139085A (ja) * 2003-11-04 2005-06-02 Ono Pharmaceut Co Ltd 顆粒
CN101111230B (zh) * 2005-03-29 2010-05-19 赢创罗姆有限责任公司 包含对活性成分具有调节释放作用的小丸的多颗粒药用形式
RU2420268C2 (ru) * 2006-09-04 2011-06-10 Панацея Биотек Лимитед Способ программируемой плавучей доставки
US20120208773A1 (en) * 2008-08-12 2012-08-16 Valeant International (Barbados) Srl Pharmaceutical compositions with tetrabenazine
JP4706785B2 (ja) * 2008-09-30 2011-06-22 アステラス製薬株式会社 経口投与用粒子状医薬組成物
KR20120022895A (ko) * 2009-04-09 2012-03-12 엘커메스 파마 아일랜드 리미티드 약물 전달 조성물
JP2013501810A (ja) * 2009-08-12 2013-01-17 ヴァリーント インターナショナル（バルバドス）エスアールエル 医薬組成物
UA119335C2 (uk) * 2013-12-11 2019-06-10 Айронвуд Фармасьютикалз, Інк. Композиції лінаклотиду з затриманим вивільненням
US20170348263A1 (en) * 2016-06-03 2017-12-07 Velicept Therapeutics, Inc. Compositions and methods of using modified release solabegron for lower urinary tract symptoms
JP6957610B2 (ja) 2016-10-06 2021-11-02 スキャンポ・アーゲーＳｕｃａｍｐｏ ＡＧ 医薬品用途のための多層ビーズ

Patent Citations (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5317032A (en) 1987-10-02 1994-05-31 Kabushiki Kaisha Ueno Seiyaku Oyo Kenkyujo Prostaglandin cathartic
US5252605A (en) * 1991-03-14 1993-10-12 R-Tech Ueno Ltd. Promotion of wound-healing with 15-keto-prostaglandin compounds
US6583174B1 (en) 1999-10-15 2003-06-24 Sucampo, A.G. Composition and method for stabilizing the same
WO2001076593A2 (fr) * 2000-04-06 2001-10-18 Sucampo Ag Composition favorisant la secretion biliaire
US6414016B1 (en) 2000-09-05 2002-07-02 Sucampo, A.G. Anti-constipation composition
WO2002089812A1 (fr) * 2001-05-02 2002-11-14 Sucampo Ag Composition comprenant des 15-ceto-prostaglandines permettant de traiter la constipation d'origine medicamenteuse
US6956056B2 (en) 2001-05-18 2005-10-18 Sucampo Ag Method for providing a cathartic effect
US7064148B2 (en) 2001-08-31 2006-06-20 Sucampo Ag Chloride channel opener
WO2007086536A2 (fr) * 2006-01-24 2007-08-02 R-Tech Ueno, Ltd. Formulation de capsule gélatineuse molle
US8026393B2 (en) 2006-01-24 2011-09-27 Sucampo Ag Soft-gelatin capsule formulation
EP2275419A2 (fr) * 2008-04-01 2011-01-19 Shanghai Techwell Biopharmaceutical Co., Ltd. Cristal de lubiprostone, son procédé de préparation et son utilisation
WO2016067620A1 (fr) 2014-10-30 2016-05-06 Sucampo Ag Procédé et composition pour le traitement de la maladie du reflux non érosif

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
"Remington's Pharmaceutical Sciences, 18th Ed.,", 1990, MACK PUBLISHING COMPANY
RIVKIN A ET AL: "Lubiprostone: Chloride channel activator for chronic constipation", CLINICAL THERAPEUTICS, EXCERPTA MEDICA, PRINCETON, NJ, US, vol. 28, no. 12, 1 December 2006 (2006-12-01), pages 2008 - 2021, XP027906858, ISSN: 0149-2918, [retrieved on 20061201] *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11534404B2 (en) 2016-10-06 2022-12-27 Sucampo Ag Multilayer beads for pharmaceutical use
US11382865B2 (en) * 2016-12-09 2022-07-12 Bayer Animal Health Gmbh Pharmaceutical preparation and method for its manufacture
JPWO2019221215A1 (ja) * 2018-05-18 2021-05-27 ニプロ株式会社 ルビプロストン含有粒子状医薬組成物
CN109701461A (zh) * 2018-10-25 2019-05-03 西南交通大学 一种基于PEG/Dex双水相的碳酸钙/海藻酸钙复合微囊的制备及其应用
CN109701461B (zh) * 2018-10-25 2021-06-08 西南交通大学 一种基于PEG/Dex双水相的碳酸钙/海藻酸钙复合微囊的制备及其应用
JP2020075874A (ja) * 2018-11-06 2020-05-21 ニプロ株式会社 ルビプロストン含有フィルム状医薬組成物

Also Published As

Publication number Publication date
TW201815383A (zh) 2018-05-01
JP6957610B2 (ja) 2021-11-02
US20200390708A1 (en) 2020-12-17
US11534404B2 (en) 2022-12-27
JP2019529467A (ja) 2019-10-17
AR109898A1 (es) 2019-02-06

Similar Documents

Publication Publication Date Title
US11534404B2 (en) Multilayer beads for pharmaceutical use
US10130580B2 (en) Taste-masked pharmaceutical compositions
US8007827B2 (en) Pharmaceutical dosage forms having immediate release and/or controlled release properties
EP1123087B1 (fr) Systeme d'administration de medicaments par doses pulsees par voie orale
US20130171199A1 (en) Controlled release pharmaceutical composition
RU2361574C2 (ru) Составы пантопразола, состоящие из множества частиц
US20080241237A1 (en) Pharmaceutical Compositions Comprising an Active Substance from the Substituted Benzhydrylpiperazine Family
US9387166B2 (en) Controlled release oral dosage form comprising oxycodone
JP2004507487A (ja) 腸疾患治療薬
JP4558207B2 (ja) クロモン腸内遊離製剤
JPH05339151A (ja) 持効性塩酸オキシブチニン製剤
US20140178484A1 (en) Multi-particulate pharmaceutical composition
US20100080846A1 (en) Dipyridamole and acetylsalicylic acid formulations and process for preparing same
US10335376B2 (en) Raloxifene sprinkle composition
WO2011040195A1 (fr) Particules masquant un goût désagréable et préparation orale les contenant
AU2006236052B2 (en) Oral pulsed dose drug delivery system
AU2004200325B2 (en) Oral Pulsed Dose Drug Delivery System
MX2008004282A (en) Pharmaceutical dosage forms having immediate release and/orcontrolled release properties

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 17808133

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 2019516182

Country of ref document: JP

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 17808133

Country of ref document: EP

Kind code of ref document: A1